12th Congress of the European Hematology ... - Haematologica

12 th Congress of the European Hematology Association
1537
DETECTION OF MOLECULAR RELAPSE OF AML BY VERY FREQUENT QUANTITATIVE
MONITORING OF DIFFERENT MOLECULAR MARKERS IN DIFFERENT COMPARTMENTS
AND ITS TREATMENT WITH CHEMOTHERAPY OR GEMTUZUMAB OZOGAMICIN
I. Palasek, M. Doubek, D. Dvorakova, Y. Brychtova, M. Borsky,
S. Struncova, M. Krejci, J. Mayer
University Hospital, BRNO, Czech Republic
Background. AML is a disease organised as a system based on the cellular
population called leukemia stem cells (LSCs), which have fundamental
importance in the origin and maintenance of the disease. We
hypothesized, that by monitoring of minimal residual disease (MRD)
and its dynamics in different compartments (peripheral blood, PB; bone
marrow, BM; and sorted CD34 + BM cells) it would be possible to find
some patterns reliably predicting clinical relapse. Aims. To find which
compartment is the best for MRD monitoring and whether it would be
possible to treat the disease in the phase of molecular relapse in order
to prevent the hematological relapse. Methods. MRD monitoring, in average
once or twice per month, was performed in all phases of treatment,
and was done even more frequently in the cases of unstable MRD. RQ
PCR for fusion transcripts (CBFB/MYH11, AML1/ETO or involving MLL
gene) and WT1 gene was used. Molecular relapse was defined as reappearance
of the fusion transcript detection or its 10-fold increase, repeatedly
detected. Some patients with already known MRD dynamics and
high probability of imminent hematological relapse were treated at the
time of molecular relapse. Results. In 67 AML patients and 6 healthy volunteers,
2352 BM or PB samples were examined, including 265 samples
from CD34 + BM cells. Follow up was 31-287 weeks (median: 113 w).
The correlation between the fusion transcripts levels in BM and PB was
excellent (r=0,9676). The correlation between WT1 PB and BM levels
was far less satisfactory. Since the WT1values were frequently >0 even
if the level of fusion transcript = 0, we wanted to find some normal value
for WT1. Using the ROC curves, however, we were not able to find
any WT1 level being a confidential marker of molecular remission in
either compartment (PB, BM or CD34 + ). The time from molecular to
haematological relapse was 8-79 days (median: 25 d). In the cases of
subsequent development of haematological relapses, the levels of fusion
transcript in CD34 + BM cells were one order of magnitude higher than
in the BM or PB, even in the case of CD34- blasts. Nine patients were
treated for 17 molecular relapses with following results: chemotherapy,
CR=2, PR=3, NR=1; gemtuzumab ozogamicin, CR=3, PR=1, NR=3; IL-
2±DLI, CR=3, NR=1 (PR was defined as a decrease in fusion transcript
level at least 10-fold). Patients with CD33- blasts at diagnosis did not
respond to gentuzumab ozogamicin. Non-responsiveness to one treatment
option did not mean non-responsiveness to another treatment.
Conclusion: Frequent quantitative monitoring (especially in CD34 + BM
cells) of fusion transcripts (in contrast to WT1) is useful for reliable prediction
of haematological relapse in AML patients. PB seems to be sufficient
for frequent outpatient MRD monitoring. Efficient targeting of
LSCs will be essential for AML cure, however, the best method is currently
not known. Some now available procedures are sometimes surprisingly
successful. Supported by Research Grant MSM 0021622430.
1538
ATRA + CHEMOTHERAPY CAN CURE MOST APL PATIENTS: LONG TERM RESULTS
OF A SINGLE CENTER EXPERIENCE
A. Ghiso, 1 M. Clavio, 1 A. Albarello, 1 M. Risso, 2 S. Biasco, 2 C. Ghiggi, 2
L. Vignolo, 2 S. Aquino, 1 N. Colombo, 1 R. Grasso, 1 R. Varaldo, 1
F. Olcese, 1 M. Miglino, 1 I. Pierri, 1 A.M. Carella, 2 M. Sessarego, 3
R. Ghio, 3 M. Gobbi1 1 Clinica Ematologica Univ. Genova, GENOVA; 2 Hematology Division S. Martino
H., GENOVA; 3 Dept. Hematology S. Martino H., GENOVA, Italy
Background and aims. since ATRA was introduced in induction therapy,
prognosis of APL patients has dramatically improved. We performed
a retrospective study on 72 consecutive, newly diagnosed APL patients
who have been treated and followed -up in a period of 15 years at the
Department of Hematology and Oncology of the S. Martino Hospital
(Genova, Italy). Patients and Methods. Cytogenetic demonstration of
t(15;17) and or detection by RT-PCR of PML-RARalfa was required for
the confirmation of diagnosis. The median age of patients was 43 years
(range 21-83). FAB subtypes were M3 in 64 patients (88%) and M3v in
8 patients (12%). The vast majority of patients had de novo APL. One
patient developed APL after NHL, while two other patients after
radiochemotherapy for breast carcinoma. According to the PETHEMA
544 | haematologica/the hematology journal | 2007; 92(s1)
scoring system, the risk was low in 16 patients (22%), intermediate in
38 (53%) and high in 18 (25%). Two patients died of brain haemorrhage
before the beginning of therapy. Nine patients were not treated initially
with ATRA as the drug was not available yet. Four of them were
treated with ATRA containing regimens due to relapse or refractory disease.
Sixty-one patients were enrolled in multicenter GIMEMA trials, all
of which included ATRA. Results. Among the 61 consecutive induction
courses there were 4 deaths during the first period of therapy (7%),
which were caused by haemorrhagic and thrombotic complications (n.
3) or infection (n. 1). Symptoms of retinoic acid syndrome were reported
in 3 patients (5%). Fifty-seven of 61 patients (92%) were evaluated
for response and all achieved CR. Forty-five patients underwent molecular
evaluation of response at the end of induction, and 35 (78%) of
them achieved molecular remission. Forty-one (67%) patients completed
the 3 consolidation courses. Following consolidation 48/49 patients
were found to have achieved molecular remission (98%). Thirty-seven
patients (60%) completed maintenance therapy and maintained molecular
remission. Nine patients (17%) relapsed, 2 with associated central
nervous system involvement. Among the relapsed patients, 2 (22%) had
the M3 variant, 4 ( 44.5%) belonged to the high risk group, only 4 had
completed consolidation course for varying reasons (44.5%) and 3 (33%)
had received maintenance therapy. Seventy-eight % of patients are
expected to be alive at 14 years from diagnosis. After a median follow
up of 96 months (4-159), median survival is 68 months (range 1-159) and
median length of CR is 60 months (range 3-157). The expected survival
at 14 years is 90% and 48% in patients with intermediate-low risk and
high risk at presentation, respectively (p= 0.0009), thus highlighting the
prognostic relevance of the PETHEMA score Eighty-nine percent of
patients who received maintenance therapy are alive and disease free at
14 years. Conclusions. a review of our long term results in the treatment
of APL in the ATRA era largely confirms that this targeted therapy has
profoundly modified the clinical outcome of this severe disease, even
though several problems still persist and need to be specifically
addressed with more tailored therapeutic strategies.
1539
SEVERE ACUTE RENAL FAILURE AS A RESULT OF TUMOR LYSIS SYNDROME AFTER
BORTEZOMIB THERAPY IN A CASE OF THERAPY-RESISTANT MULTIPLE MYELOMA
S. Stankovic
University Clinical center, SKOPJE, Macedonia
Background. The proteasome inhibitor bortezomib, has antimyeloma
activity even in myeloma cells refractory to multiple prior treatments.
Frequently described side effects are gastrointestinal symptoms, fatigue,
neuropathy and thrombocytopenia. Clinical trials have not indicated
severe nephrotoxicity with this agent. Aims. To report our experience
with bortezomib and a very severe, unexpected side effect after the
administration of this medication. Methods. A 62-year old male patient
with a therapy resistant IgG type multiple myeloma, stage III-A, was
treated with bortezomib. For the past 6 years he had been treated with
melphalan-containing protocols (VMPC, VBMCP and ABCM), then with
thalidomide, and had a refractory disease. Prior to treatment with bortezomib
the patient had documented increments of serum monoclonal
component IgG 38.4g/l, bone marrow infiltration with 45% plasma cells
and normal renal function. Results. The patient was treated with bortezomib
started as a single-agent therapy planning the 3-weekly regimen
(1.3mg/m (2) at days 1, 4, 8 and 11, followed by rest for 10 days). We
noticed a slight increase in serum creatinine value after the administration
of the first dose of bortezopmib when coricosteroids and hidratation
were started. But, serum creatinine and BUN (blood urea nitrogen)
levels continued to increase with the next three doses of bortezomib
(creatinine 165, 420 and 588 micromol/l and BUN 12.9, 15.5 and
23.8mmol/l respectively). There was a prompt deterioration of renal
function with oliguria, hyperkalemia (5.6 mmol/l) hypocalcemia
(1.8mmol/l) and hyperphosphatemia (2.4 mmol/l). The patient was
admitted to the Department of nephrology where dialyses 3 times
weekly were started. Markers of tubular damage (NAG, AAP and gamaGT)
were also elevated. The clinical condition of the patient had been
worsening from day to day with an extreme prostration and paroxysmal
tachycardia and the patient died within one month. Conclusions. To
our knowledge this is the first report of life-threatening renal failure
after bortezomib in a patient with refractory myeloma. Even more, there
are several reports of reversal of renal failure at patients with myeloma
and renal failure after the treatment with bortezomib. These findings
suggest that a bortezomib-indused rapid reduction in tumor burden may
lead to tumor lysis syndrome so that, caution is always needed when
threatening myeloma patients with this very effective agent.